RuâCatalyzed Regioselective Cascade Annulation of Acrylamides

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Ru#Catalyzed Regioselective Cascade Annulation of Acrylamides with 2-Alkynoates for the Synthesis of Various 6-Oxo Nicotinic Acid Esters Dnyaneshwar Nilkanth Garad, and Santosh B. Mhaske J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02783 • Publication Date (Web): 15 Jan 2019 Downloaded from http://pubs.acs.org on January 15, 2019

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The Journal of Organic Chemistry

Ru‒Catalyzed Regioselective Cascade Annulation of Acrylamides with 2Alkynoates for the Synthesis of Various 6-Oxo Nicotinic Acid Esters Dnyaneshwar N. Garad†‡ and Santosh B. Mhaske†‡* †

Division of Organic Chemistry, CSIR-National Chemical Laboratory, Pune- 411008, India Academy of Scientific and Innovative Research (AcSIR), Ghaziabad- 201002, India

‡

Supporting Information Placeholder ABSTRACT: Ru‒catalyzed regioselective cascade annulation of acrylamides with 2-alkynoates via azaMichael/C‒H activation sequence for the synthesis of various 6-oxo nicotinic acid esters is described. The regioselectivity of the protocol has been confirmed by performing silver mediated protodecarboxylation of the corresponding 6-oxo nicotinic acid to furnish 2-pyridone. The developed protocol is copper or silver salt-free and uses inexpensive, safe, and environmentally benign peroxide-based ‘Oxone’ as the sole oxidant. Redox-neutral version of the protocol is also demonstrated.

INTRODUCTION Pyridone is an ubiquitous scaffold in biologically active molecules.1 In particular, 6-oxo nicotinic acid esters and hydroxypyridinecarboxylic acids constitute biologically important class of compounds.2 They are used for metal chelation therapy because of their good binding capacity towards aluminum(III) and iron(III). Milrinone, ciclopirox, pirfenidone, cytisine, flavipucine, camptothecin (CPT) and perampanel are some of the important natural products and pharmaceuticals featuring pyridone core1-3 (Fig.1). As a result, several methods for the selective preparation of these heterocycles and their derivatives are reported in the literature.1a,b,2a,4 Among these

Figure 1. Selected Pyridone Containing Natural Products and Drugs

Methods, C‒H Bond activation has emerged as a cost and step-economical tool for the synthesis of the pyridone class of

N-heterocycles.5 Transition-metal-catalyzed oxidative annulation of amides with alkynes by C-H bond activation is one of the most commonly used methods for the synthesis of pyridones6 and isoquinolones.7 Oxidative annulation of benzamides with alkynes have been explored more than that of acrylamides using various metal catalysts. Previously, ruthenium and rhodium catalytic systems have been employed on acrylamides and unsymmetrical alkynes for the regioselective synthesis of β-alkyl pyridones (Scheme 1, eq 1).6e,f Recently, Fan and co-workers reported Rh-catalyzed redox neutral annulation protocol for the annulation of benzoyl and acryloyl hydroxamates with ynoates possessing a tertiary propargyl alcohol for the regioselective synthesis of -lactone ring-fused pyridones (Scheme 1, eq 2).8 The regioselectivity of this protocol was accomplished by the chelation of metal catalyst with hydroxyl group present in the ynoates. The literature known strategies5-8 mostly follow C-H activation/alkyne insertion sequence to form C‒C bond followed by C‒N bond formation via reductive elimination to get 3-alkyl substituted pyridones. We envisioned that RuCl2(p-cymene) catalyzed reaction might follow aza-Michael/C‒H activation sequence with 2-alkynoates due to the high electron withdrawing nature of the ester moiety to accomplish complete reverse regioselectivity on contrary to the known ruthenium or rhodium catalyzed protocols with aryl(alkyl)acetylenes. In this context, we have developed a protocol for inverse regioselective oxidative annulation of acrylamides with 2-alkynoates for the synthesis of various 6-oxo nicotinic acid esters (α-alkyl pyridones) using ruthenium catalysis (Scheme 1 eq 3). We further describe few

ACS Paragon Plus Environment

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Scheme 1. Annulation of Acrylamides with unsymmetrical Alkynes/2-Alkynoates

control reactions, which shed some light on the regioselectivity and mechanism of this transformation. RESULTS AND DISCUSSION We began to optimize the oxidative coupling by employing Nphenyl acrylamide (1a) and ethyl 2-butynoate (2a, Table 1). First, we attempted the literature known oxidative annulation conditions6f with [RuCl2(p-cymene)]2 catalyst and copper acetate in t-amyl alcohol but ended up in the complex reaction mixture, and the expected product 3a was not observed (entry 1). Interestingly, the change in the solvent from t-amyl alcohol to DCE resulted in the expected product formation though in Table 1. Optimization Studies

catalyst

additive (equiv)

oxidant (equiv)

solvent/temp

(mol%)

1

5

-

Cu(OAc)2 (2)

TAA/120

--

2

5

-

Cu(OAc)2 (2)

DCE/100

18%

3

5

-

Cu(OAc)2 (2)

1,4-dioxane/110

22%

4

5

KOAc (0.1)

K2S2O8 (2)

1,4-dioxane/110

35%

5

5

KOAc (0.1)

Oxone (2)

1,4-dioxane/110

45%

6

5

KOAc (0.1)

Oxone (2)

1,4-dioxane/100

35%

7

5

KOAc (0.1)

Oxone (2)

1,4-dioxane/120

40%

8

2

KOAc (0.1)

Oxone (2)

1,4-dioxane/110

30%

9

10

KOAc (0.1)

Oxone (2)

1,4-dioxane/110

46%

10

20

KOAc (0.1)

Oxone (2)

1,4-dioxane/110

44%

entrya,b

a

(oC)

KOAc additive and nonmetallic oxidant K2S2O8 was used with Ru-catalyst [RuCl2(p-cymene)]2, a substantial increment in the yield was observed (entry 4). Pleasingly, a clean reaction was observed (entry 5) when catalytic [RuCl2(p-cymene)]2 and KOAc along with Oxone was used as the oxidant. The known annulation protocols usually require stoichiometric amounts of mostly metallic oxidants, which compromises the overall sustainable nature of C−H bond activation process.5,6 The use of inexpensive and non-metallic oxidants in such protocols is still rare.9 Herein, we have demonstrated its use in the regioselective annulation protocol using ruthenium catalysis. Further deviation in the reaction temperature (entries 6, 7) or variation in the catalyst loading (entries 8-10) did not show considerable improvement in the yield. The probable reason for the low yield of this transformation could be the instability of the starting materials at a higher temperature under the present conditions and volatile nature of 2a. To check the stability of alkynoates we subjected 2a to our reaction condition in the absence of 1a and observed decomposition of 2a. Only 45% of 2a could be recovered after 24 h. Thus, the optimum condition for this transformation is as follows: [RuCl2(p-cym)]2 (5 mol%), KOAc (10 mol%), Oxone (2 equiv) in 1,4-dioxane at 110 oC. After having optimal conditions in hand, we turned our attention to the evaluation of the scope of the reaction (Scheme 2). The protocol has been generalized to access varyingly subScheme 2. Ru-Catalyzed Annulation of Various Acrylamides with ethyl 2-butynoatea,b

Resultc

b

Selected entries. Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), [RuCl2(p-cym)]2 (5 mol%), KOAc (10 mol%), oxidant (0.6 mmol), 1,4 dioxane (3 mL) in glass tube for 30 h at 110 oC. c Isolated yield. TAA = t-amyl alcohol.

low yield (entry 2). Remarkably, single regioisomer formation was observed in the reaction. When the reaction was performed in 1,4-dioxane at 110 oC, little improvement in the yield was observed (entry 3). To our delight, when 10 mol%

a

Reaction conditions: 1 (0.3 mmol), 2a (0.6 mmol), [RuCl2(pcym)]2 (5 mol%), KOAc (10 mol%), Oxone (0.6 mmol), 1,4 dioxane (3 mL) in glass tube for 30 h at 110 oC. bIsolated yield. c10 mmol scale reaction, dReaction with N-Acetyl acrylamide, eReaction was carried out at 120 oC in sealed tube for 40 h.


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The Journal of Organic Chemistry stituted 6-oxo nicotinic acid esters. Initially, N-aryl substituted pyridones were synthesized using various N-aryl substituted acrylamides and ethyl 2-butynoate (2a). As mentioned in the optimization studies, the N-phenyl substituted acrylamide furnished pyridone 3a in 45% yield. We also performed the reaction of 1a with 2a at the 10 mmol scale and observed consistency in the yield (44%) of 3a. The N-(p-tolyl) substituted acrylamide delivered pyridone 3b in moderate yield under the developed protocol. The N-(3-(trifluoromethyl) phenyl)acrylamide and N-(3-fluorophenyl)acrylamide smoothly underwent oxidative annulation with 2a and furnished the corresponding pyridones 3c and 3d respectively in acceptable yields. Electron withdrawing ester group and electron releasing methoxy group at the para position of phenyl ring attached to the nitrogen of acrylamide did not affect much on annulation reaction and analogous pyridones 3e and 3f were obtained in modest yields. Various N-alkyl substituted acrylamides have also been used for the oxidative annulation with 2a and resulted into formation of N-benzyl 3g, N-Methyl 3h, and Npropyl 3i pyridones in better yields as compared to the N-aryl acrylamides. The NMR yield of the crude reaction mixture of 3h is consistent with the isolated yield (see SI). Whereas, annulation of acrylamide and alkynoate 2a produced pyridone 3j in 30% yield. The formation of pyridone 3j was also observed when N-acetyl acrylamide was used as the substrate. Acetyl group deprotection was observed under these conditions and 3j was isolated in 25% yield. The data of 3j is in agreement with the literature report,10 which confirms the regioselectivity of our protocol. The effect of substituents on the various position of N-methyl acrylamide was also studied and varyingly methyl substituted pyridones 3k and 3l were synthesized with reasonable yields. It should be noted that for the synthesis of pyridones 3k and 3l, a higher reaction temperature and longer reaction time were required and these reactions were performed in a sealed tube. The higher temperature required for these substrates may be due to the steric effect of methyl substituents at the β-position of acrylamides. After having studied the substrate scope with respect to various N-substituted acrylamides, we decided to study the substrate scope with various 2-alkynoates (Scheme 3). The Scheme 3. Ru-Catalyzed Annulation of N-Me/Ph Acrylamides with 2-Alkynoatesa,b

a

Reaction conditions: 1a/h (0.3 mmol), 2 (0.6 mmol), [RuCl2(pcym)]2 (5 mol%), KOAc (10 mol%), Oxone (0.6 mmol), 1,4 dioxane (3 mL) in glass tube for 30 h at 110 oC. bIsolated yield. cReaction was carried out at 120 oC in a sealed tube for 40 h.

reaction of N-phenyl acrylamide and ethyl 2-pentynoate conceded pyridone 3m in moderate yield. As observed above in the substrate scope studies (Scheme 2) N-methyl acrylamide furnished the highest yield of pyridone 3h, hence for further studies N-methyl acrylamide was chosen as a fixed substrate and reacted with various alkynoates. The pyridones with various substituents at the second position such as ethyl 3n, decyl 3o, cyclopropyl 3p, and cyclopentyl 3q were synthesized in low to moderate yields from the corresponding alkynoates. For the synthesis of pyridones, 3p and 3q also higher temperature and more time was required, and these reactions were performed in a sealed tube. Probably, steric hindrance of cyclopropyl and cyclopentyl rings of 2-alkynoate affects the rate of annulation. After having studied the substrate scope of oxidative annulation protocol with the external oxidant, we decided to study oxidant free annulation reaction of acrylamides and 2alkynoates (Scheme 4). One solution to overcome the use of an external oxidizing reagent involves the development of redox-neutral versions with hydroxamates.7f,g When the Nmethoxy acrylamide 1n was reacted with ethyl 2-butynoate (2a) at room temperature without external oxidant, the corresponding N-H free pyridone 3j was obtained in 45% yield. Comparison of the NMR spectral data of 3j with those described in the literature10 for this compound confirms the structure of this latter compound and the regioselectivity of the Scheme 4. Ru-Catalyzed Redox-Neutral Annulation of NMethoxy Acrylamide with 2-Alkynoates

ruthenium-catalyzed annulation. The N-H free pyridone 3r was also synthesized by employing redox neutral strategy using N-methoxy acrylamide 1n and ethyl 2-pentynoate as substrates. Here, the substrate itself acts as an oxidant and no external oxidant is required for these reactions. The developed protocol worked very well with various acrylamides but unfortunately, it did not work with benzamides. The regioselectivity of our protocol was also confirmed by synthesizing 6-methyl-1-phenylpyridin-2(1H)-one (Scheme 5A). Initially, ester hydrolysis of pyridone 3a was carried out using aqueous NaOH in ethanol to obtain acid 4a in excellent yield. The acid 4a was then subjected under various protodecarboxylation conditions. Under the silver carbonate mediated condition in N,N-dimethylacetamide it furnished the pyridone 5a in 42% yield. The NMR spectral data of compound 5a were consistent with those described in the literature.11 This reconfirms our hypothesis and regioselectivity of this protocol. Additionally it shows utility of our method for the synthesis of 2-oxopyridones. The direct synthesis of 2oxopyridones using phenyl acetylene/ethyl propiolate was not possible under the developed condition, which demonstrates the importance of the present protocol. During the substrate scope study, we utilized 2-alkynoates having α-hydrogens. We were curious to know the outcome of the protocol in the absence of α-hydrogen. Interestingly, when R4 of 2-alkynoates is phenyl/tertiary butyl/ester (Scheme 5B), the expected products were not observed, which could be mostly due to ste-



ric/electronic factors. However, the protocol works well when R4 is the primary or secondary alkyl group, which suggests that the possible involvement of allene intermediates in the reaction cannot be ruled out. The HRMS study of the reaction mixture was also carried out to detect the possible intermediates of the reaction (Scheme 5C), and interestingly M+H peak of ruthenacycle II was detected by HRMS analysis. Scheme 5. Control Reactions

A plausible reaction mechanism is proposed based on the above experimental outcome (Scheme 6) and literature reports.7d,e Initially, ligand exchange of ruthenium catalyst and

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CONCLUSION In summary, Ruthenium catalyzed reverse regioselective annulation of acrylamides with alkynes than that of aryl(alkyl)acetylenes has been developed. The reverse regioselectivity and tentative mechanism is supported by controlled experiments. The annulation protocol is further extended as the redox neutral process, where the substrate acts as an oxidant for the metal catalyst. Diverse novel 6-oxo nicotinic acid esters have been synthesized using the developed protocol. Further improvement in the protocol to access various 6-oxo nicotinic acid esters in higher yields and its application in the synthesis of natural products and bioactive molecules is under progress in our laboratory. EXPERIMENTAL SECTION General Information. All reagents and solvents were used as received from commercial sources unless otherwise noted. All experiments were carried out under an argon atmosphere in a glass tube with side arm or Teflon screw cap glass tube. Aluminum plates precoated with silica gel 60 PF254, 0.25 mm or 0.5 mm were utilized for thin-layer chromatography (TLC). Column chromatographic purifications were carried out on flash silica gel (240−400 mesh) using petroleum ether and ethyl acetate as the eluents. The 1H and 13C{1H}NMR spectra were recorded on 400 MHz and 100 MHz NMR spectrometer, respectively, in CDCl3 or DMSO-d6. Chemical shifts were reported as δ values from standard peaks. The mass spectra were taken on an LC−MS (ESI) mass spectrometer. Highresolution mass spectrometry (HRMS) was performed on a TOF/Q-TOF mass spectrometer. N-alkyl and N-alkoxy substituted acrylamides,12 N-aryl substituted acrylamides13 and commercially unavailable 2-alkynoate14 starting materials were prepared according to literature procedures.

FOR

RU‒

Scheme 6. Proposed Mechanism

EXPERIMENTAL PROCEDURES CATALYZED ANNULATION

amide N-directed C-H bond activation of acrylamide 1 forms ruthenacycle I followed by insertion of alkynoate 2 by azamichael type of addition to furnish the ruthenacycle intermediate II (detected by HRMS when R1 = R4 = Me). Product 3 could be formed after reductive elimination of metal from ruthenacycle II. The oxidation of Ru(0) to Ru(II) by Oxone makes the active catalyst available for further catalytic cycles.

General Procedure-1. To a mixture of [RuCl2(p-cymene)]2 (0.015 mmol; 9.2 mg) and KOAc (0.03 mmol; 3 mg) in a glass tube with side arm was added 1,4-dioxane (3 mL; 0.1M) under argon atmosphere and the reaction mixture was stirred for 1 h at room temperature (rt). Acrylamide 1a-m (0.3 mmol), 2alkynoate 2a-e (0.6 mmol) and Oxone (0.6 mmol; 185 mg) were added to the above mixture and the glass tube was placed in a preheated oil bath at 110 oC for stipulated time. The progress of the reaction was monitored by TLC. After complete consumption of acrylamide 1a-m (30-40 h), the reaction mixture was cooled to rt, diluted with ethyl acetate, filtered through a short pad of celite, and the filtrate was evaporated under vacuo to dryness. The resulting residue was purified by column chromatography to afford pure pyridones 3a-q. General Procedure-2. To a mixture of [RuCl2(p-cymene)]2 (0.015 mmol; 9.2 mg) and KOAc (0.03 mmol; 3 mg) in glass tube with side arm was added 1,4-dioxane (3 mL; 0.1M) under argon atmosphere and the reaction mixture was stirred for 1 h at rt. Acrylamide 1n (0.3 mmol) and 2-alkynoate 2a/b (0.6 mmol) were added to the above mixture and it was stirred at rt. The progress of the reaction was monitored by TLC. After complete consumption of acrylamide 1n (24 h), the reaction mixture was diluted with ethyl acetate, filtered through a short pad of celite, and the filtrate was evaporated under vacuo to dryness. The resulting residue was purified by column chromatography to afford pure pyridones 3j/r.


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The Journal of Organic Chemistry Procedure for the Preparation of Pyridone 3a on 10 mmol Scale. To a mixture of [RuCl2(p-cymene)]2 (0.5 mmol; 306 mg) and KOAc (1 mmol; 98 mg) in a two-neck round-bottom flask was added 1,4-dioxane (100 mL; 0.1M) under argon atmosphere and the reaction mixture was stirred for 1 h at rt. N-Phenyl arylamide (1a, 10 mmol; 1.47 gm), ethyl 2butynoate (2a, 20 mmol; 2.24 mL) and Oxone (20 mmol; 6.15 gm) were added to the above mixture and the glass tube was placed in preheated oil bath at 110 oC for 30 h. The progress of the reaction was monitored by TLC. After complete consumption of acrylamide 1a (30 h) the reaction mixture was cooled to rt, diluted with ethyl acetate, filtered through short pad of celite, and the filtrate was evaporated under vacuo to dryness. The resulting residue was purified by column chromatography to afford pure pyridone 3a (1.13 g; 44%). Ethyl 2-methyl-6-oxo-1-phenyl-1,6-dihydropyridine-3carboxylate (3a). According to the general procedure-1, the title compound 3a was obtained as a thick oil (35 mg; 45% yield); reaction time: 30 h; Rf: 0.5 (2:3 EtOAc: Pet. ether); 1H NMR (400 MHz, CDCl3) δ (ppm) 7.98 (d, J = 9.8 Hz, 1H), 7.55 (t, J = 7.3 Hz, 2H), 7.48 (t, J = 7.3 Hz, 1H), 7.16 (d, J = 7.3 Hz, 2H), 6.53 (d, J = 9.8 Hz, 1H), 4.32 (q, J = 6.7 Hz, 2H), 2.37 (s, 3H), 1.37 (t, J = 6.7 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 165.5, 163.3, 153.9, 140.4, 138.4, 130, 129.1, 127.7, 117.3, 109.2, 60.9, 19.7, 14.3; HRMS (ESITOF) m/z: [M+Na]+ calcd for C15H15O3NNa 280.0944, found 280.0943. Ethyl 2-methyl-6-oxo-1-(p-tolyl)-1,6-dihydropyridine-3carboxylate (3b). According to the general procedure-1, the title compound 3b was obtained as a thick oil (34 mg; 42% yield); reaction time: 30 h; Rf: 0.5 (2:3 EtOAc: Pet. ether); 1H NMR (400 MHz, CDCl3) δ (ppm) 7.97 (d, J = 9.6 Hz, 1H), 7.34 (d, J = 8.7 Hz, 2H), 7.04 (d, J = 8.3 Hz, 2H), 6.53 (d, J = 9.2 Hz, 1H), 4.31 (q, J = 7.3 Hz, 2H), 2.43 (s, 3H), 2.38 (s, 3H), 1.37 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 165.6, 163.4, 154.2, 140.3, 139.1, 135.7, 130.7, 127.4, 117.2, 109.2, 60.9, 21.2, 19.7, 14.3; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C16H18O3N 272.1281, found 272.1280. Ethyl 2-methyl-6-oxo-1-(3-(trifluoromethyl)phenyl)-1,6dihydropyridine-3-carboxylate (3c). According to the general procedure-1, the title compound 3c was obtained as a thick oil (46 mg; 47% yield); reaction time: 30 h; Rf: 0.5 (2:3 EtOAc: Pet. ether); 1H NMR (400 MHz, CDCl3) δ (ppm) 8.01 (d, J = 9.8 Hz, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.70 (t, J = 7.9 Hz, 1H), 7.47 (s, 1H), 7.40 (d, J = 7.9 Hz, 1H), 6.55 (d, J = 9.8 Hz, 1H), 4.33 (q, J = 7.3 Hz, 2H), 2.37 (s, 3H), 1.38 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 165.3, 163, 153.2, 140.9, 138.9, 132.7 (q, J = 33 Hz), 131.6, 130.7, 126.2 (q, J = 3 Hz), 125.1 (q, J = 3 Hz), 123.3 (q, J = 273 Hz), 117.5, 109.9, 61.1, 19.8, 14.3; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C16H14O3NF3Na 348.0818, found 348.0815. Ethyl 1-(3-fluorophenyl)-2-methyl-6-oxo-1,6-dihydropyridine3-carboxylate (3d). According to the general procedure-1, the title compound 3d was obtained as a thick oil (35 mg; 42% yield); reaction time: 30 h; Rf: 0.5 (2:3 EtOAc: Pet. ether); 1H NMR (400 MHz, CDCl3) δ (ppm) 7.99 (d, J = 10.1 Hz, 1H), 7.57-7.48 (m, 1H), 7.21 (td, J = 8.2, 2.8 Hz, 1H), 6.98 (dt, J = 7.8, 1 Hz, 1H), 6.94 (dt, J = 8.7, 2.3 Hz, 1H), 6.53 (d, J = 9.6 Hz, 1H), 4.33 (q, J = 6.9 Hz, 2H), 2.40 (s, 3H), 1.38 (t, J = 6.9 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 165.4, 163.3 (d, J = 249.2 Hz), 163, 153.5, 140.7, 139.7 (d, J = 10.5

Hz), 131.3 (d, J = 8.6 Hz), 123.8 (d, J = 2.9 Hz), 117.4, 116.4 (d, J = 20.1 Hz), 115.7 (d, J = 23 Hz), 109.5, 61.1, 19.6, 14.3; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C15H15O3NF 276.1030, found 276.1028. Ethyl 1-(4-(methoxycarbonyl) phenyl)-2-methyl-6-oxo-1,6dihydropyridine-3-carboxylate (3e). According to the general procedure-1, the title compound 3e was obtained as a thick oil (44 mg; 47% yield); reaction time: 30 h; Rf: 0.5 (2:3 EtOAc: Pet. ether); 1H NMR (400 MHz, CDCl3) δ (ppm) 8.23 (d, J = 8.7 Hz, 2H), 7.99 (d, J = 10.1 Hz, 1H), 7.27 (d, J = 8.7 Hz, 2H), 6.54 (d, J = 9.6 Hz, 1H), 4.32 (q, J = 7.3 Hz, 2H), 3.96 (s, 3H), 2.37 (s, 3H), 1.38 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 165.96, 165.4, 162.98, 153.2, 142.4, 140.7, 131.4, 130.96, 128.1, 117.4, 109.5, 61.1, 52.4, 19.7, 14.3; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C17H18O5N 316.1179, found 316.1178. Ethyl 1-(4-methoxyphenyl)-2-methyl-6-oxo-1,6dihydropyridine-3-carboxylate (3f). According to the general procedure-1, the title compound 3f was obtained as a thick oil (39 mg; 45% yield); reaction time: 30 h; Rf: 0.5 (2:3 EtOAc: Pet. ether); 1H NMR (400 MHz, CDCl3) δ (ppm) 7.97 (d, J = 9.6 Hz, 1H), 7.09-7.03 (m, 4H), 6.54 (d, J = 9.6 Hz, 1H), 4.32 (q, J = 6.9 Hz, 2H), 3.86 (s, 3H), 2.40 (s, 3H), 1.38 (t, J = 6.9 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 165.6, 163.6, 159.8, 154.4, 140.4, 130.9, 128.7, 117.2, 115.2, 109.3, 60.9, 55.5, 19.7, 14.3; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C16H18O4N 288.1230, found 288.1227. Ethyl 1-benzyl-2-methyl-6-oxo-1,6-dihydropyridine-3carboxylate (3g). According to the general procedure-1, the title compound 3g was obtained as a thick oil (45 mg; 55% yield); reaction time: 30 h; Rf: 0.5 (2:3 EtOAc: Pet. ether); 1H NMR (400 MHz, CDCl3) δ (ppm) 7.94 (d, J = 9.6 Hz, 1H), 7.35-7.25 (m, 3H), 7.13 (d, J = 7.3 Hz, 2H), 6.56 (d, J = 9.6 Hz, 1H), 5.45 (s, 2H), 4.29 (q, J = 6.9 Hz, 2H), 2.72 (s, 3H), 1.36 (t, J = 6.9 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 165.7, 163.2, 153.9, 140.1, 135.7, 128.9, 127.5, 126.3, 116.6, 109.9, 60.96, 47.5, 17.7, 14.3; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C16H18O3N 272.1281, found 272.1279. Ethyl 1,2-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylate (3h). According to the general procedure-1, the title compound 3h was obtained as a thick oil (34 mg; 58% yield); reaction time: 30 h; Rf: 0.5 (1:1 EtOAc: Pet. ether); 1H NMR (400 MHz, CDCl3) δ (ppm) 7.87 (d, J = 9.8 Hz, 1H), 6.45 (d, J = 9.8 Hz, 1H), 4.29 (q, J = 7.3 Hz, 2H), 3.60 (s, 3H), 2.78 (s, 3H), 1.35 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 165.7, 163.2, 153.6, 139.6, 116, 109.6, 60.9, 31.6, 17.9, 14.2; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C10H14O3N 196.0968, found 196.0967. Ethyl 2-methyl-6-oxo-1-propyl-1,6-dihydropyridine-3carboxylate (3i). According to the general procedure-1, the title compound 3i was obtained as a thick oil (32 mg; 48% yield); reaction time: 30 h; Rf: 0.5 (1:1 EtOAc: Pet. ether); 1H NMR (400 MHz, CDCl3) δ (ppm) 7.84 (d, J = 9.8 Hz, 1H), 6.42 (d, J = 9.8 Hz, 1H), 4.28 (q, J = 7.3 Hz, 2H), 4.06 (t, J = 7.3 Hz, 2H), 2.80 (s, 3H), 1.77-1.64 (m, 2H), 1.35 (t, J = 7.3 Hz, 3H), 1.01 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 165.8, 162.9, 153, 139.6, 116.5, 109.5, 60.9, 46.2, 21.6, 17.2, 14.3, 11.3; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C12H18O3N 224.1281, found 224.1280. Ethyl 2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (3j).10 According to the general procedure-1 and by using acrylamide and N-acetyl acrylamide, the title compound 3j



was obtained as a thick oil (16 mg; 30% yield) and (14 mg; 25% yield) respectively; reaction time: 30 h; whereas by using general procedure-2 and N-methoxy acrylamide, the title compound 3j was obtained as a thick oil (25 mg; 45% yield); reaction time: 24 h; Rf: 0.4 (2:1 EtOAc: Pet. ether); 1H NMR (400 MHz, CDCl3) δ (ppm) 12.92 (bs, 1H), 8.06 (d, J = 9.8 Hz, 1H), 6.43 (d, J = 9.8 Hz, 1H), 4.31 (q, J = 7.3 Hz, 2H), 2.74 (s, 3H), 1.37 (t, J =7.6 Hz, 3H), 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 165.3, 164.8, 152.9, 143, 116, 109.4, 60.8, 19.7, 14.3; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C9H12O3N 182.0812, found 182.0811. Ethyl 1,2,4-trimethyl-6-oxo-1,6-dihydropyridine-3-carboxylate (3k). According to the general procedure-1 at 120 oC in the glass tube with screw cap, the title compound 3k was obtained as a thick oil (24 mg; 38% yield); reaction time: 40 h; Rf: 0.5 (1:1 EtOAc: Pet. ether); 1H NMR (400 MHz, CDCl3) δ (ppm) 6.32 (s, 1H), 4.34 (q, J = 7.3 Hz, 2H), 3.52 (s, 3H), 2.39 (s, 3H), 2.17 (s, 3H), 1.37 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 167.8, 162.6, 147.4, 145.7, 117.1, 114.8, 61.4, 31.1, 20.4, 18.5, 14.2; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C11H16O3N 210.1125, found 210.1123. Ethyl 1,2,4,5-tetramethyl-6-oxo-1,6-dihydropyridine-3carboxylate (3l). According to the general procedure-1 at 120 oC in the glass tube with screw cap, the title compound 3l was obtained as a thick oil (27 mg; 40% yield); reaction time: 40 h; Rf: 0.5 (1:1 EtOAc: Pet. ether); 1H NMR (400 MHz, CDCl3) δ (ppm) 4.35 (q, J = 7.3 Hz, 2H), 3.55 (s, 3H), 2.34 (s, 3H), 2.12 (s, 6H), 1.38 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 168.6, 162.9, 141.7, 140.7, 123.8, 115.5, 61.4, 31.7, 18.2, 17.3, 14.2, 13; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C12H18O3N 224.1281, found 224.1279. Ethyl 2-ethyl-6-oxo-1-phenyl-1,6-dihydropyridine-3carboxylate (3m). According to the general procedure-1, the title compound 3m was obtained as a thick oil (31 mg; 38% yield); reaction time: 30 h; Rf: 0.5 (2:3 EtOAc: Pet. ether); 1H NMR (400 MHz, CDCl3) δ (ppm) 8.01 (d, J = 9.8 Hz, 1H), 7.59-7.47 (m, 3H), 7.20 (d, J = 6.8 Hz, 2H), 6.52 (d, J = 9.8 Hz, 1H), 4.32 (q, J = 6.8 Hz, 2H), 2.84 (q, J = 6.8 Hz, 2H), 1.38 (t, J = 7.5 Hz, 3H), 1.04 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 165, 163.5, 159.4, 140.9, 137.9, 129.7, 129.1, 128.2, 117.3, 108.2, 60.9, 24.8, 14.3, 13.7; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C16H18O3N 272.1281, found 272.1279. Ethyl 2-ethyl-1-methyl-6-oxo-1,6-dihydropyridine-3carboxylate (3n). According to the general procedure-1, the title compound 3n was obtained as a thick oil (25 mg; 40% yield); reaction time: 30 h; Rf: 0.5 (1:1 EtOAc: Pet. ether); 1H NMR (400 MHz, CDCl3) δ (ppm) 7.89 (d, J = 9.8 Hz, 1H), 6.45 (d, J = 9.2 Hz, 1H), 4.29 (q, J = 6.7 Hz, 2H), 3.64 (s, 3H), 3.22 (q, J = 7.3 Hz, 2H), 1.36 (t, J = 6.7 Hz, 3H), 1.30 (t, J =7.3 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 165.3, 163.4, 158.2, 139.9, 116.2, 108.7, 60.8, 30.96, 24, 14.2, 12.5; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C11H16O3N 210.1125, found 210.1123. Ethyl 2-decyl-1-methyl-6-oxo-1,6-dihydropyridine-3carboxylate (3o). According to the general procedure-1, the title compound 3o was obtained as a thick oil (34 mg; 35% yield); reaction time: 30 h; Rf: 0.5 (1:1 EtOAc: Pet. ether); 1H NMR (400 MHz, CDCl3) δ (ppm) 7.89 (d, J = 9.8 Hz, 1H), 6.44 (d, J = 9.8 Hz, 1H), 4.29 (q, J = 6.7 Hz, 2H), 3.63 (s, 3H), 3.16 (t, J =7.3 Hz, 2H), 1.66-1.57 (m, 2H), 1.51-1.43 (m, 2H), 1.36 (t, J = 7.3 Hz, 3H), 1.31-1.22 (m, 12H), 0.89 (t, J = 6.7

Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 165.4, 163.5, 157.6, 139.9, 116.1, 108.8, 60.8, 31.9, 31.1, 30.7, 29.8, 29.5, 29.3, 29.2, 28.4, 22.7, 14.3, 14.1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C19H32O3N 322.2377, found 322.2374. Ethyl 2-cyclopropyl-1-methyl-6-oxo-1,6-dihydropyridine-3carboxylate (3p). According to the general procedure-1 at 120 oC in the glass tube with screw cap, the title compound 3p was obtained as a thick oil (18 mg; 28% yield); reaction time: 40 h; Rf: 0.5 (1:1 EtOAc: Pet. ether); 1H NMR (400 MHz, CDCl3) δ (ppm) 7.63 (d, J = 9.8 Hz, 1H), 6.49 (d, J = 9.8 Hz, 1H), 4.32 (q, J = 7.3 Hz, 2H), 3.74 (s, 3H), 2.05-1.95 (m, 1H), 1.37 (t, J = 7.3 Hz, 3H), 1.23 (apparent q, J = 6.1 Hz, 2H), 0.63 (apparent q, J = 6.1 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 166.4, 163.3, 154.7, 139.1, 117.3, 113.3, 61.2, 32.7, 14.3, 14.25, 9.9; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C12H16O3N 222.1125, found 222.1124. Ethyl 2-cyclopentyl-1-methyl-6-oxo-1,6-dihydropyridine-3carboxylate (3q). According to the general procedure-1 at 120 oC in the glass tube with screw cap, the title compound 3q was obtained as a thick oil (19 mg; 26% yield); reaction time: 40 h; Rf: 0.5 (1:1 EtOAc: Pet. ether); 1H NMR (400 MHz, CDCl3) δ (ppm) 7.76 (d, J = 9.9 Hz, 1H), 6.51 (d, J = 9.9 Hz, 1H), 4.40-4.25 (m, 3H), 3.57 (s, 3H), 2.11-1.98 (m, 4H), 1.971.86 (m, 4H), 1.36 (t, J = 6.9 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 166.7, 163.97, 158, 140, 116, 111.9, 61.2, 40.1, 34.2, 30.7, 27, 14.2; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C14H20O3N 250.1438, found 250.1436. Ethyl 2-ethyl-6-oxo-1,6-dihydropyridine-3-carboxylate (3r). According to the general procedure-2, the title compound 3r was obtained as a thick oil (23 mg; 40% yield); reaction time: 24 h; Rf: 0.4 (2:1 EtOAc: Pet. ether); 1H NMR (400 MHz, CDCl3) δ (ppm) 12.68 (bs, 1H), 8.03 (d, J = 9.9 Hz, 1H), 6.42 (d, J = 9.2 Hz, 1H), 4.32 (q, J = 7.6 Hz, 2H), 3.11 (q, J = 7.6 Hz, 2H), 1.37 (t, J = 7.6 Hz, 3H), 1.34 (t, J = 7.6 Hz, 3H); 13 C{1H} NMR (100 MHz, CDCl3) δ (ppm) 165.5, 164.7, 158.2, 143.1, 116.4, 108.2, 60.8, 26.1, 14.2, 13.9; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C10H14O3N 196.0968, found 196.0968. 2-Methyl-6-oxo-1-phenyl-1,6-dihydropyridine-3-carboxylic acid (4a). To a round bottom flask containing the solution of ester 3a (1 mmol, 257 mg) in EtOH (20 mL) was added 2N aqueous NaOH (10 mL) at rt. The resulting mixture was stirred at rt until completion of the reaction (2h). The reaction mixture was then diluted with water and transferred to a separating funnel and washed with ethyl acetate (2 x 5 mL). The aqueous layer was acidified to pH 2 with dil. HCl and extracted with EtOAc (3 x 20 mL). The organic layer was dried over Na2SO4 and evaporated under vacuo to dryness to afford pure acid 4a (202 mg; 88% yield), which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 12.77 (bs, 1H), 7.94 (d, J = 9.8 Hz, 1H), 7.55 (t, J = 7.3 Hz, 2H), 7.48 (t, J = 7.3 Hz, 1H), 7.28 (d, J = 7.3 Hz, 2H), 6.40 (d, J = 9.8 Hz, 1H), 2.28 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ (ppm) 166.8, 162.2, 153.9, 140.9, 138.6, 129.6, 128.7, 128.2, 116.4, 108.7, 19.4; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C13H12O3N 230.0812, found 230.0810. 6-Methyl-1-phenylpyridin-2(1H)-one (5a).11 A glass tube with side arm was charged with acid 4a (0.1 mmol, 23 mg), Ag2CO3 (0.2 mmol, 55 mg), PivOH (0.15 mmol, 15 µL), Na2CO3 (0.4 mmol, 43 mg) and DMA (1 mL). The glass tube was placed in preheated oil bath at 120 oC for 24 h. After 24 h, the reaction was cooled to rt, diluted with ethyl acetate and


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The Journal of Organic Chemistry filtered through a short pad of celite. The filtrate was washed two times with water, dried over Na2SO4 and evaporated under vacuo to dryness. The resulting residue was purified by column chromatography to afford pure pyridone 5a (8 mg; 42%); Rf: 0.3 (1:1 EtOAc: Pet. ether); 1H NMR (400 MHz, CDCl3) δ (ppm) 7.56-7.50 (m, 2H), 7.48-7.43 (m, 1H), 7.31 (dd, J = 9.2, 6.9 Hz, 1H), 7.23-7.18 (m, 2H), 6.55 (d, J = 9.2 Hz, 1H), 6.11 (d, J = 6.9 Hz, 1H), 1.96 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 164, 146.4, 139.6, 138.8, 129.8, 128.8, 127.8, 118.5, 106.1, 21.6; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C12H12ON 186.0913, found 186.0914. HRMS Study of Ruthenacycle (II). A glass tube with side arm was charged with [RuCl2(p-cymene)] (0.02 mmol; 12 mg) and KOAc (0.04 mmol; 4 mg) under argon atmosphere. To this reaction mixture 1,4-dioxane (4 mL; 0.1M) was added and stirred for 1 h at rt. N-Methyl acrylamide 1h (0.2 mmol), ethyl 2-butynoate 2a (0.4 mmol) and Oxone (0.4 mmol) were added to the mixture and it was stirred at 110 oC for 1 h. The reaction mixture was immediately subjected to mass analysis. HRMS of Ruthenacycle(II) (ESI-TOF) m/z: [M+H]+ calcd for C20H28O3NRu 432.1107, found 432.1104.

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ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: Spectroscopic data (1H, 13C{1H} spectra) of all new compounds (PDF) (5)

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]

ORCID Santosh B. Mhaske: 0000-0002-5859-0838 (6)

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT D.N.G. thanks UGC-New Delhi for the research fellowship, and S.B.M. gratefully acknowledges generous financial support from DST-SERB, New Delhi.

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